Continuum Approaches to Understanding Ion and Peptide Interactions with the Membrane
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Experimental and computational studies have shown that cellular membranes deform to stabilize the inclusion of transmembrane (TM) proteins harboring charge. Recent analysis suggests that membrane bending helps to expose charged and polar residues to the aqueous environment and polar head groups. We previously used elasticity theory to identify membrane distortions that minimize the insertion of charged TM peptides into the membrane. Here, we extend our work by showing that it also provides a novel, computationally efficient method for exploring the energetics of ion and small peptide penetration into membranes. First, we show that the continuum method accurately reproduces energy profiles and membrane shapes generated from molecular simulations of bare ion permeation at a fraction of the computational cost. Next, we demonstrate that the dependence of the ion insertion energy on the membrane thickness arises primarily from the elastic properties of the membrane. Moreover, the continuum model readily provides a free energy decomposition into components not easily determined from molecular dynamics. Finally, we show that the energetics of membrane deformation strongly depend on membrane patch size both for ions and peptides. This dependence is particularly strong for peptides based on simulations of a known amphipathic, membrane binding peptide from the human pathogen Toxoplasma gondii. In total, we address shortcomings and advantages that arise from using a variety of computational methods in distinct biological contexts.
KeywordsIon permeation Membrane elasticity Continuum Coarse grained Rhoptry protein 5 (ROP5)
We would like to thank Nwamaka Onyeozili, Siyu Xiao, Mary Krawczak, and Shuchang Liu for their assistance in setting up and running initial variations of the coarse-grained MD simulations. We also thank Frank Marcoline for help implementing the dipole potential, and John Rosenberg, Daniel Zuckerman, Patrick Van der Wel, Joshua Adelman and Charles Wolgemuth for enlightening discussions. Naomi R. Latorraca was supported by an Undergraduate Research Fellowship from the Howard Hughes Medical Institute, and this work was supported by an NSF CAREER Award (MCB-0722724) to Michael Grabe and a Pew Scholarship in the Biomedical Sciences to Jon P. Boyle. We dedicate this work to Harold Lecar, a deep scholar, incredible teacher and good friend.
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